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      Genetics of rheumatoid arthritis contributes to biology and drug discovery

      research-article
      1 , 2 , 3 , * , 1 , 2 , 3 , 4 , 5 , 1 , 2 , 3 , 2 , 3 , 6 , 7 , 8 , 9 , 10 , 8 , 10 , 9 , 11 , 11 , 11 , 11 , 12 , 13 , 12 , 13 , 14 , 15 , 16 , 17 , 17 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 3 , 26 , 28 , 3 , 3 , 29 , 1 , 2 , 3 , 1 , 2 , 3 , 1 , 2 , 3 , 1 , 3 , 27 , 10 , 7 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 25 , 34 , 34 , 40 , 41 , 42 , 43 , 44 , 45 , 45 , 46 , 47 , 48 , 49 , 50 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , the RACI consortium, the GARNET consortium, 57 , 58 , 57 , 58 , 57 , 59 , 60 , 61 , 1 , 9 , 62 , 63 , 4 , 45 , 57 , 58 , 64 , 64 , 65 , 1 , 2 , 3 , 66 , 67 , 68 , 2 , 3 , 6 , 25 , 19 , 20 , 19 , 9 , 8 , 69 , 17 , 11 , 21 , 22 , 23 , 9 , 7 , 70 , 71 , 10 , 72 , 1 , 2 , 3 , *
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          Abstract

          A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA) 1 . Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 24 . We devised an in-silico pipeline using established bioinformatics methods based on functional annotation 5 , cis-acting expression quantitative trait loci (cis-eQTL) 6 , and pathway analyses 79 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes – to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

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          Most cited references14

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          The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.

          The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.
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            The pathogenesis of rheumatoid arthritis.

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              • Article: not found

              A human phenome-interactome network of protein complexes implicated in genetic disorders.

              We performed a systematic, large-scale analysis of human protein complexes comprising gene products implicated in many different categories of human disease to create a phenome-interactome network. This was done by integrating quality-controlled interactions of human proteins with a validated, computationally derived phenotype similarity score, permitting identification of previously unknown complexes likely to be associated with disease. Using a phenomic ranking of protein complexes linked to human disease, we developed a Bayesian predictor that in 298 of 669 linkage intervals correctly ranks the known disease-causing protein as the top candidate, and in 870 intervals with no identified disease-causing gene, provides novel candidates implicated in disorders such as retinitis pigmentosa, epithelial ovarian cancer, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer disease, type 2 diabetes and coronary heart disease. Our publicly available draft of protein complexes associated with pathology comprises 506 complexes, which reveal functional relationships between disease-promoting genes that will inform future experimentation.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                25 December 2013
                25 December 2013
                20 February 2014
                20 August 2014
                : 506
                : 7488
                : 376-381
                Affiliations
                [1 ]Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
                [2 ]Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
                [3 ]Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
                [4 ]Department of Statistics, Harvard University, Cambridge, MA, USA.
                [5 ]Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
                [6 ]Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA.
                [7 ]Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
                [8 ]Department of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
                [9 ]Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan.
                [10 ]Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
                [11 ]Immunology Biomarkers Group, Genentech, South San Francisco, CA, USA.
                [12 ]Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA.
                [13 ]Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
                [14 ]New York University Hospital for Joint Diseases, New York, NY, USA.
                [15 ]Department of Medicine, Albany Medical Center and The Center for Rheumatology, Albany, NY, USA.
                [16 ]Division of Rheumatology, Department of Medicine, New York, Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
                [17 ]Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
                [18 ]Department of Pharmacology, Second Military Medical University, Shanghai, 200433, China
                [19 ]University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
                [20 ]Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
                [21 ]Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.
                [22 ]Toronto General Research Institute, Toronto, Canada.
                [23 ]Department of Medicine, University of Toronto, Toronto, Canada.
                [24 ]Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Canada.
                [25 ]Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands.
                [26 ]Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia.
                [27 ]Division of Endocrinology, Children’s Hospital, Boston, MA, USA.
                [28 ]School of Computer and Information Technology, Beijing Jiaotong University, Beijing, China.
                [29 ]The Department of Psychiatry at Mount Sinai School of Medicine, New York, USA.
                [30 ]Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
                [31 ]Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
                [32 ]Department of Rheumatology and Clinical Immunology, Arthritis Center Twente, University Twente & Medisch Spectrum Twente, Enschede, The Netherlands.
                [33 ]Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
                [34 ]Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
                [35 ]Service de Rhumatologie et INSERM U699 Hôpital Bichat Claude Bernard, Assistance Publique des Hôpitaux de Paris, Paris, France.
                [36 ]Université Paris 7-Diderot, Paris, France.
                [37 ]Université Paris-Sud, Orsay, France.
                [38 ]APHP–Hôpital Bicêtre, INSERM U1012, Le Kremlin Bicêtre, Paris, France.
                [39 ]Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
                [40 ]AMC/University of Amsterdam, Amsterdam, the Netherlands.
                [41 ]GlaxoSmithKline, Stevenage, U.K.
                [42 ]University of Cambridge, Cambridge, U.K.
                [43 ]Institut National de la Santé et de la Recherche Médicale (INSERM) U1012.
                [44 ]Université Paris-Sud 11, Rhumatologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France.
                [45 ]Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea.
                [46 ]Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
                [47 ]Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander, Spain.
                [48 ]Hospital Clinico San Carlos, Madrid, Spain.
                [49 ]Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
                [50 ]Department of Rheumatology, Umeå University, Umeå, Sweden.
                [51 ]Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
                [52 ]Section of Rheumatology, Boston University School of Medicine, Boston, MA, USA.
                [53 ]Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, MA, USA.
                [54 ]Centre d’Etude du Polymorphisme Humain (CEPH), Paris, France.
                [55 ]Université Paris 13 Sorbonne Paris Cité, UREN (Nutritional Epidemiology Research Unit), Inserm (U557), Inra (U1125), Cnam, Bobigny, France.
                [56 ]McGill University and Génome Québec Innovation Centre, Montréal, Canada.
                [57 ]Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
                [58 ]National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
                [59 ]Department of Clinical Immunology and Rheumatology & Department of Genome Analysis, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
                [60 ]Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
                [61 ]Rosalind Russell Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
                [62 ]Unit of Statistical Genetics, Center for Genomic Medicine Graduate School of Medicine Kyoto University, Kyoto, Japan.
                [63 ]Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
                [64 ]Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
                [65 ]The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, NY, USA.
                [66 ]NIHR Manchester Musculoskeletal Biomedical, Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
                [67 ]Section of Genetic Medicine, University of Chicago, Chicago, IL, USA.
                [68 ]Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, USA.
                [69 ]Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
                [70 ]Core Research for Evolutional Science and Technology (CREST) program, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.
                [71 ]Institut National de la Sante et de la Recherche Medicale (INSERM) Unite U852, Kyoto University Graduate School of Medicine, Kyoto, Japan.
                [72 ]Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
                Author notes
                [* ]Correspondence authors: Robert M. Plenge and Yukinori Okada, Robert M. Plenge, MD, PhD, Director, Genetics & Genomics, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Suite 168, Boston, MA 02115, USA., Telephone: +1-617-525-4451, Fax: +1-617-525-4488, robert.plenge@ 123456merck.com , Yukinori Okada, MD, PhD, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Suite 255, Boston, MA 02115, USA., Telephone: +1-617-525-4055, Fax: +1-617-525-4488, yokada@ 123456broadinstitute.org
                [73]

                Full list of contributing authors for the RACI and GARNET consortia is provided in Supplementary Information.

                Article
                NIHMS539022
                10.1038/nature12873
                3944098
                24390342
                f50bc6d3-815c-4084-8a52-26b647fd63e8

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